PROCESS FOR THE PREPARATION OF OXCARBAZEPINE AND ITS USE AS INTERMEDIATE IN THE PREPARATION OF ESLICARBAZEPINE ACETATE
Field of the Invention
The present invention provides a process for the preparation of oxcarbazepine,
which is an Active Pharmaceutical Ingredient (API), and a useful intermediate in the
preparation of eslicarbazepine acetate. The present invention further provides a process
for the preparation of eslicarbazepine acetate.
Background of the Invention
lO-oxo-10,1 l-dihydro-5 H-dibenzo[Z J ]azepine-5-carboxamide of Formula 1,
commonly known as oxcarbazepine, is an antiepileptic drug marketed under the trade
name Trileptal®. Oxcarbazepine is also an intermediate in the preparation of
eslicarbazepine acetate.
Formula 1
U.S. Patent No. 3,642,775 provides a process for the preparation of oxcarbazepine
which involves refluxing 10-methoxy-5H-dibenz[Z J ]azepine-5-carboxamide with 2N
hydrochloric acid for 2 hours. Oxcarbazepine was isolated from the reaction mixture by
cooling, filtering, and finally recrystallizing from ethanol with a yield of 80%.
PCT Publication No. WO 96/21649 provides a process for the preparation of
oxcarbazepine which involves refluxing 10-methoxy-5H-dibenz[Z J ]azepine-5-
carboxamide with 10% sulfuric acid for 2 hours to 3 hours. Oxcarbazepine was isolated
from the reaction mixture by cooling, filtering, washing with water, and finally
recrystallizing from dimethylacetamide.
PCT Publication No. WO 01/56992 provides a process for the preparation of
oxcarbazepine which involves adding water and 100% sulfuric acid to a mixture of 10-
methoxy-5H-dibenzo[Z J ]azepine-5-carboxamide in acetic acid until the pH is less than 1,
and then stirring the reaction mixture for 17 hours. Oxcarbazepine was isolated from the
reaction mixture by adding water and filtering the precipitated oxcarbazepine, with a yield
of 78%.
PCT Publication No. WO 02/096881 provides a process for the preparation of
oxcarbazepine which involves oxidation of 10, 11-dihydro- 10-hydroxy-5Hdibenzo[
Z J ]azepine-5-carboxamide with peroxyacetic acid in the presence of potassium
dichromate adsorbed on silica gel at room temperature.
U.S. Patent No. 7,459,553 (herein after referred to as U.S. '553) provides a process
for the preparation of oxcarbazepine which involves adding 2N hydrochloric acid to 10-
methoxycarbamazepine in dichloromethane and maintaining the reaction mixture at about
40°C to 50°C for about 4 hours to 6 hours. Oxcarbazepine was isolated from the reaction
mixture by cooling the reaction mixture to 0°C to 5°C and filtering the separated solid.
Another process for the preparation of oxcarbazepine involves adding 2N hydrochloric
acid to 10-methoxycarbamazepine and maintaining the reaction mixture at about 80°C to
85°C for about 4 hours to 5 hours. Oxcarbazepine was isolated from the reaction mixture
by cooling the reaction mixture to 50°C, adding toluene and maintaining the reaction
mixture at 50°C for 30 minutes, then further cooling the reaction mixture to about 25°C to
30°C and filtering the solid. The oxcarbazepine obtained by the second process provided
in U.S. '553 has a purity of 97% to 98% and requires further purification.
U.S. Patent No. 6,670,472 (herein after referred to as U.S. '472) provides a process
for the preparation of oxcarbazepine which involves treating 10-methoxyiminostilbene
with either benzoic acid and sodium cyanate, />chlorobenzoic acid and sodium cyanate,
2,4-dichloro benzoic acid and sodium cyanate or benzoic acid and potassium cyanate, the
product of which was then hydrolyzed with either 2N hydrochloric acid, 2N sulphuric
acid, or 2N monochloroacetic acid to obtain oxcarbazepine. The oxcarbazepine thus
obtained by the processes provided in U.S. '472 involves further purification in a mixture
of dichloromethane :methanol, dichloromethane :toluene or toluene:methanol.
PCT Publication No. WO 2005/066133 provides a process for the preparation of
oxcarbazepine which involves dissolving 10-methoxy-5H-dibenzo[Z J ]azepine-5-
carboxamide in ethylene dichloride, adding o-toluene sulfonic acid and maintaining the
reaction mixture at about 75°C to 80°C for about 3 hours. Oxcarbazepine was isolated
from the reaction mixture by cooling the reaction mixture to 20°C, filtering, and further
purifying using acetone-water.
PCT Publication No. WO 2005/092862 provides a process for the preparation of
oxcarbazepine which involves adding water to a stirred suspension of 10-methoxy-5Hdibenzo[
Z J ]azepine-5-carboxamide and 37% hydrochloric acid at pH 1 and stirring at
95°C for 4 hours. Oxcarbazepine was isolated from the reaction mixture by cooling to
25°C, adding 30% sodium hydroxide until pH was 7.0 to 7.5, filtering, and washing with
water. The oxcarbazepine thus obtained was again purified to attain a purity of 99%.
EP Publication No. EP 1600443 provides a process for the preparation of
oxcarbazepine which involves hydrolysis of 10-methoxy-N-aminocarbonyl-iminostilbene
by refluxing with 10% sulfuric acid for one hour. Oxcarbazepine was isolated from the
reaction mixture by cooling to room temperature, filtering, washing with water, and
further recrystallizing from dimethylformamide.
PCT Publication No. WO 2007/141798 provides a process for the preparation of
oxcarbazepine which involves hydrolysis of 10-methoxy-5H-dibenzo[Z J ]azepine-5-
carboxamide in toluene and water with concentrated hydrochloric acid at a temperature of
75°C to 80°C. Oxcarbazepine was isolated from the reaction mixture by cooling the
reaction mixture, filtering, washing with toluene, and washing with 5% sodium
bicarbonate and water. The oxcarbazepine thus obtained was purified twice using
methanol and methanol/dichloromethane, respectively.
PCT Publication No. WO 2009/139001 provides a process for the preparation of
oxcarbazepine which involves heating 10-methoxycarbamazepine in water and oxalic acid
at 90°C for about 17 hours. Oxcarbazepine was isolated from the reaction mixture by
cooling the reaction mixture to room temperature, filtering, washing with water, and
further purifying using isopropyl alcohol and water.
Several other processes are known in the literature for making oxcarbazepine, for
example, U.S. Patent No. 4,452,738; and PCT Publication Nos. WO 2010/000196, WO
2008/012837, WO 2006/075925, WO 2005/122671, WO 2005/1 18550, WO 2005/096709,
WO 03/106414, and WO 00/55138; and Organic Process Research &Development, 9(3),
272-277 (2005).
Eslicarbazepine acetate of Formula A, chemically known as (10S)-5-carbamoyl-
10,1 l-dihydro-5 H-dibenzo[¾/]azepin-10-yl acetate is indicated as adjunctive therapy in
adults with partial-onset seizures with or without secondary generalisation.
Formula A
Several processes are known in the literature for making and purifying
eslicarbazepine acetate, for example, PCT Publication Nos. WO 2006/005951, WO
2007/1 17166, and WO 2010/1 13 179, Journal of Medicinal Chemistry, 42(14), 2582-2587
(1999).
U.S. Patent No. 5,753,646 provides a process for the preparation of eslicarbazepine
acetate which involves the drop-wise addition of a solution of acetyl chloride in
dichloromethane to a suspension of (-)- 10-hydroxy- 10,1l-dihydro-5 Hdibenzo[
Z J ]azepine-5-carboxamide in dichloromethane and pyridine at a temperature of
less than 10°C under stirring. The residue obtained after work up was crystallized from a
mixture of dichloromethane and ethyl acetate to give the eslicarbazepine acetate as white
crystals.
PCT Publication No. WO 02/092572 provides a process for the preparation of
eslicarbazepine which involves optical resolution of racemic (±)- 10,1 1-dihydro- 10-
hydroxy-5 H-dibenzo[Z J ]azepine-5-carboxamide using diacetyl tartaric anhydride.
PCT Publication No. WO 2004/031 155 (herein after WO 55) provides a process
for the preparation of eslicarbazepine which involves enantioselective transfer
hydrogenation of oxcarbazepine using triethyl amine and formic acid in the presence of
RuCl[(l S,2S -TsNCH(C6H )CH(C 6H )NH2] -/J-cymene) in dichloromethane at reflux
temperature. The present inventors observed that the process provided in WO 55 leads
to degradation and only 60% to 70% of the reaction is completed in 17 hours. Further, the
process requires flash chromatography to isolate eslicarbazepine from the reaction
mixture. Thus, the process is not commercially viable.
PCT Publication No. WO 2006/056339 provides a process for the preparation of
eslicarbazepine which involves hydrolysis of (S)-(+)-5-cyano-10,l 1-dihydro- 10-hydroxy-
5H-dibenzo[Z J ]azepine using peroxy compounds such as sodium perborate or hydrogen
peroxide in alkaline medium.
PCT Publication No. WO 2007/012793 provides a process for the preparation of
eslicarbazepine which involves asymmetric reduction of oxcarbazepine using
triethylamine and formic acid at a pH range of 6.5 to 8 in the presence of a catalyst
generated in situ by the reaction of RuCi2(p-cymene)] 2 and (S,S)-TsDAEN.
PCT Publication No. WO 201 1/091 13 1 provides a process for the preparation of
eslicarbazepine which involves optical resolution of racemic (±)- 10,1 1-dihydro- 10-
hydroxy-5 H-dibenzo[Z J ]azepine-5-carboxamide using naproxen. It also provides another
process for the preparation of eslicarbazepine which involves asymmetric reduction of
oxcarbazepine using a borane dimethyl sulfide complex in the presence of R-MeCBS.
PCT Publication No. WO 201 1/131315 provides processes for the preparation of
eslicarbazepine which involve asymmetric transfer hydrogenation of oxcarbazepine in the
presence of catalysts such as, RuCl [(S,S)-Ts-DPEN](p-cymene), RuCl [(S,S)-Ms-
DPEN](p-cymene), RuCl [(S,S)-teth-TsDPEN], RuCl [(S,S)-Fs-DPEN](p-cymene) and an
ion exchange resin such as IRA-67 tertiary ion exchange resin. An alternative process for
the preparation of eslicarbazepine involves asymmetric transfer hydrogenation of
oxcarbazepine in the presence of catalyst RuCl [(S,S)-Ts-DPEN](p-cymene) and a
quaternary amine such as tetramethylammonium hydroxide.
Journal of Molecular Catalysis B: Enzymatic, 72, 294-297 (201 1) provides a
process for the preparation of eslicarbazepine which involves asymmetric reduction of
oxcarbazepine with an enzyme, Saccharomyces cerevisiae CGMCC No. 2266. According
to this publication, the optimum reaction time was 36 hours, optimum reaction
temperature was 30°C, optimum initial reaction pH was 7, and a continuous reduction
method was preferred to obtain eslicarbazepine.
Journal of American Chemical Society, 118(10), 252 1-2522 ( 1996) provides the
use of ruthenium complexes such as [(S,S)-TsDpen-Ru(p-cymene)Cl] as catalysts and
triethylamine/formic acid as a hydrogen donor for the enantioselective reduction of simple
ketones.
The present inventors identified that oxcarbazepine prepared by the hydrolysis of
10-methoxy-5H-dibenzo[Z J ]azepine-5-carboxamide using hydrochloric acid, sulfuric acid,
or acetic acid results in a low yield and chromatographic purity. Therefore, further
purification of oxcarbazepine would be necessary to improve the quality of the product.
Further reagents such as hydrochloric acid, sulfuric acid, and acetic acid are corrosive in
nature and are therefore undesirable.
Extensive experimentation has been carried out by controlling parameters such as
the combination of solvents in various ratios, reagents/catalysts which are highly efficient,
commercially available, and economically feasible for developing an improved process for
the preparation of oxcarbazepine and eslicarbazepine.
Thus, the present invention provides an efficient, industrially preferable, and
economic process for preparing oxcarbazepine and eslicarbazepine in good yield with
excellent chemical and enantiomeric purity. The present invention further provides
eslicarbazepine acetate in good yield, with excellent chemical and enantiomeric purity.
The present inventors have developed an improved process for the preparation of
oxcarbazepine and eslicarbazepine which avoids the excess usage of environmentally
hazardous reagents and organic solvents, thereby promoting green chemistry and ensuring
cleaner surroundings by putting a lesser load on the environment.
Summary of the Invention
One aspect of the present invention provides a process for the preparation of
eslicarbazepine acetate of Formula A
Formula A
which comprises
a) hydrolysis of 10-methoxy-5H-dibenzo[Z?/]azepine-5-carboxamide of
Formula 3
Formula 3
with an organic acid selected from the group consisting of citric acid, tartaric
acid, or mixtures thereof to obtain oxcarbazepine of Formula 1;
Formula 1
b) asymmetric transfer hydrogenation of the oxcarbazepine of Formula 1 in the
presence of a catalyst and a hydride source in a mixture of
dichloromethane/NN -dimethylformamide, dichloromethane/water, or
dichloromethane/water/methanol to obtain eslicarbazepine of Formula 2; and
Formula 2
c) acylation of the eslicarbazepine of Formula 2 to obtain eslicarbazepine
acetate of Formula A.
Another aspect of the present invention provides a process for the preparation of
oxcarbazepine of Formula 1
which comprises hydrolysis of 10-methoxy-5H-dibenzo[Z J ]azepine-5-carboxamide of
Formula 3
Formula 3
with an organic acid selected from the group consisting of citric acid, tartaric acid, or
mixtures thereof.
Detailed Description of the Invention
One aspect of the present invention provides a process for the preparation of
eslicarbazepine acetate of Formula A
Formula A
which comprises:
a) hydrolysis of 10-methoxy-5H-dibenzo[Z J ]azepine-5-carboxamide of
Formula 3
Formula 3
with an organic acid selected from the group consisting of citric acid, tartaric
acid, or mixtures thereof to obtain oxcarbazepine of Formula 1;
Formula 1
asymmetric transfer hydrogenation of the oxcarbazepine of Formula 1 in the
presence of a catalyst and a hydride source in a mixture of
dichloromethane/NN -dimethylformamide, dichloromethane/water, or
dichloromethane/water/methanol to obtain eslicarbazepme of Formula 2; and
c) acylation of eslicarbazepme of Formula 2 to obtain eslicarbazepme acetate of
Formula A.
In one embodiment of this aspect, step a) is performed in one or more solvent.
The "solvent" is selected from the group consisting of water, esters, aromatic
hydrocarbons, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, or
mixtures thereof.
Examples of esters include ethyl acetate, n-propyl acetate, isopropyl acetate, and nbutyl
acetate. Examples of aromatic hydrocarbons include toluene and xylene. Examples
of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-
dichloroethane. Examples of ketones include acetone and methyl ethyl ketone. Examples
of ethers include diethyl ether and tetrahydrofuran. Examples of polar aprotic solvents
include N N-dimethylformamide, N N-dimethylacetamide, dimethylsulphoxide,
acetonitrile, and N-methylpyrrolidone.
The hydrolysis of 10-methoxy-5H-dibenzo[Z J ]azepine-5-carboxamide of Formula
3 in step a) is performed at a temperature of 30°C to reflux for a time period sufficient to
complete the reaction. After completion of the reaction, oxcarbazepine may be isolated by
a common isolation technique such as cooling, extraction, washing, crystallization,
precipitation, filtration, filtration under vacuum, decantation and centrifugation, or
combinations thereof.
The isolated oxcarbazepine may be optionally purified by crystallization or
chromatographic methods, or combinations thereof, before proceeding to step b).
In one embodiment of this aspect, step b) may be performed optionally in the
presence of a phase transfer catalyst.
A suitable phase transfer catalyst may be tetra-«-butylammonium bromide.
The catalyst is selected from the group consisting of [(S,S)-TsDpen-Ru(pcymene)
Cl], [(S,S)-teth-TsDpen-RuCl], RuCl [(S,S)-FsDPEN](p-cymene), RuCl[(S,S)-
TsDPEN](mesitylene). The molar ratio of the catalyst to oxcarbazepine may be from
about 0.0005 to about 0.1.
The hydride source is selected from the group consisting of sodium acetate/water,
formic acid/triethyl amine, potassium-/-butoxide/isopropanol, potassium
hydroxide/isopropanol, ammonium formate, and ammonium acetate. The molar ratio of
the hydride source to oxcarbazepine may be from about 0.1 to about 8.
After the completion of the reaction, eslicarbazepine may be isolated by a common
isolation technique such as cooling, extraction, washing, crystallization, precipitation,
filtration, filtration under vacuum, decantation and centrifugation, or combinations thereof.
The isolated eslicarbazepine may be optionally purified by crystallization or
chromatographic methods, or combinations thereof, before proceeding to step c).
In another embodiment of this aspect, acylation of eslicarbazepine of Formula 2 in
step c) involves treating eslicarbazepine with an acylating agent in the presence of a
catalyst in one or more solvents at a temperature of 25°C to reflux for a time period
sufficient to complete the reaction.
The term "treating" includes adding, dissolving, slurrying, stirring, or
combinations thereof.
The acylating agent is selected from the group consisting of acetic anhydride or
acetyl chloride. A suitable catalyst may be 4-Dimethylaminopyridine.
After completion of the reaction, eslicarbazepine acetate of Formula A may be
optionally isolated by a common isolation technique such as cooling, extraction, washing,
crystallization, precipitation, filtration, filtration under vacuum, decantation and
centrifugation, or combinations thereof.
The isolated eslicarbazepine acetate may be optionally purified by crystallization
or chromatographic methods, or combinations thereof.
Another aspect of the present invention provides a process for the preparation of
oxcarbazepine of Formula 1,
Formula 1
which comprises hydrolysis of 10-methoxy-5H-dibenzo[b,f]azepine-5-carboxamide of
Formula 3
Formula 3
with an organic acid selected from the group consisting of citric acid, tartaric acid, or
mixtures thereof.
In one embodiment of this aspect, the hydrolysis of 10-methoxy-5Hdibenzo[
Z J ]azepine-5-carboxamide of Formula 3 is performed in one or more solvents.
The "solvent", as used herein, has the same meaning as defined above.
The hydrolysis of 10-methoxy-5H-dibenzo[Z J ]azepine-5-carboxamide of Formula
3 is performed at a temperature of 30°C to reflux temperature for a time period sufficient
to complete the reaction.
After the completion of the reaction, oxcarbazepine can be isolated by a common
isolation technique such as cooling, extraction, washing, crystallization, precipitation,
filtration, filtration under vacuum, decantation and centrifugation, or combinations thereof.
The isolated oxcarbazepine may be optionally purified by crystallization or
chromatographic methods, or combinations thereof.
The oxcarbazepine obtained according to the present invention may be used as an
Active Pharmaceutical Ingredient (API) and may be formulated into finished
pharmaceutical products. Alternatively, it can be converted to eslicarbazepine or
eslicarbazepine acetate by the methods exemplified herein or methods known in the art.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the
art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1: Preparation of oxcarbazepine
10-methoxy-5H-dibenzo[Z J ]azepine-5-carboxamide (2 g, 0.0075 mol) was added
to 10% aqueous tartaric acid (20 mL) at 25°C to 30°C under stirring. The reaction mixture
was heated to 95°C to 100°C and stirred for 2 hours. The reaction mixture was then
cooled to 25°C to 30°C and stirred at 25°C to 30°C for 3 hours. The solid was filtered,
washed with deionized water (20 mL), and dried at 50°C to 55°C until constant weight
was achieved to obtain the title compound.
Yield: 1.7 g (90.42%)
Chromatographic Purity: 99.39%
Example 2 : Preparation of oxcarbazepine
10-methoxy-5H-dibenzo[Z J ]azepine-5-carboxamide ( 1 g, 0.00375 mol) was added
to 5% aqueous citric acid (10 mL) at 25°C to 30°C under stirring. The reaction mixture
was heated to 95°C to 100°C and stirred for 2 hours. The reaction mixture was then
cooled to 25°C to 30°C and deionized water (15 mL) was added and stirred at 25°C to
30°C for 3 hours. The solid was filtered, washed with deionized water (10 mL), and dried
at 50°C to 55°C until constant weight was achieved to obtain the title compound.
Yield: 0.88 g (93.6%)
Chromatographic Purity: 99.24%
Example 3: Preparation of oxcarbazepine
10-methoxy-5H-dibenzo[Z J ]azepine-5-carboxamide ( 1 g, 0.00375 mol) was added
to 5% aqueous acetic acid (10 mL) at 25°C to 30°C under stirring. The reaction mixture
was heated to 95°C to 100°C and stirred for 3 hours. The reaction mixture was then
cooled to 25°C to 30°C, and the solid was filtered, washed with deionized water (10 mL),
and dried at 50°C to 55°C until constant weight was achieved to obtain the title compound.
Yield: 0.81 g (85.2%)
Chromatographic Purity: 98.85%
Example 4 : Preparation of oxcarbazepine
10-methoxy-5H-dibenzo[Z J ]azepine-5-carboxamide (5 g, 0.0187 mol) was charged
to 5% aqueous citric acid (50 mL; 2.5 g citric acid in 50 mL water). Toluene (25 mL) was
charged to the reaction mixture and heated to reflux (86°C). The reaction mixture was
stirred for 12 hours at 86°C. The reaction mixture was cooled to 25°C to 30°C and stirred
for 2 hours. The solid was filtered and dried for 2 hours at 50°C to 55°C to obtain the title
compound.
Yield: 4.4 g (93%)
Chromatographic Purity: 99.72% (0.12% unreacted 10-methoxy carbamazepine)
Example 5 : Preparation of oxcarbazepine
2N aqueous hydrochloric acid (50 mL) was added to 10-methoxy-5Hdibenzo[
Z J ]azepine-5-carboxamide (5.0 g, 0.0187 mol) at 25°C to 30°C and was stirred
for 10 minutes. The reaction mixture was heated to 95°C to 100°C for 2 hours. After
completion of the reaction, the reaction mixture was cooled to 10°C to 15°C and stirred for
15 minutes to 20 minutes. The solid was filtered and washed with water (15 mL). The
solid was suck dried and further dried at 50°C to 55°C under vacuum for 15 hours to
obtain crude oxcarbazepine.
Yield: 4.3 g (90.15%)
Chromatographic Purity: 96.53%
The crude oxcarbazepine was suspended in denatured spirits (10 mL) and the
resulting slurry was heated to reflux for 30 minutes. The suspension was cooled to 0°C to
5°C and stirred for 1 hour. The solid was isolated by filtration and dried under vacuum to
obtain the title compound.
Yield: 3.7 g (77.56%)
Chromatographic Purity: 97.89%
Example 6 : Preparation of eslicarbazepine
[(S,S)-TsDpen-Ru(p-cymene)Cl] (52 mg, 0.000081 mol) was added to a stirred
suspension of oxcarbazepine (5.0 g, 0.01983 mol) and dichloromethane (200 mL) at 25°C
to 30°C under nitrogen followed by the drop-wise addition of a premixed solution of
formic acid and triethyl amine (4.8 mL:8 mL) in dichloromethane (50 mL). After stirring
at 25°C to 30°C for 15 minutes, the reaction mixture was heated to reflux (39°C to 42°C)
for 4 days. The pH of the reaction mixture was maintained at 5.4 to 6.5 by the addition of
formic acid (0.8 mL). After completion of the reaction, the reaction mixture was
concentrated under reduced pressure to 50 mL and hexane (200 mL) was charged
dropwise and stirred for 3 hours at 25°C to 30°C. The reaction mixture was filtered and
washed with hexane (10 mL). The solid obtained was suck dried and further dried at 50°C
to 55°C for 5 hours to obtain the title compound.
Yield: 4.4 g (88%)
Chromatographic Purity: 99.58%
Chiral purity: 99.4%
Example 7 : Preparation of eslicarbazepine acetate
4-Dimethylaminopyridine (0.06 g, 0.00047 mol) was added to a stirred suspension
of the eslicarbazepine obtained in Example 6 (2.0 g, 0.0079 mol) in acetone (12 mL) at
25°C to 30°C. The reaction mixture was stirred at 25°C to 30°C and acetic anhydride (1.1
g, 0.0102 mol) was added to it. The reaction mixture was stirred at 25°C to 30°C for 2
hours. After completion of the reaction, deionized water (36 mL) was charged drop-wise
and stirred for 3 hours at 18°C to 20°C. The reaction mixture was filtered, then washed
with deionized water (4 mL). The solid thus obtained was suck dried and further dried at
50°C to 55°C for 12 hours to obtain the title compound.
Yield: 1.81 g (78.7%)
Chromatographic Purity: 99.41%,
Chiral purity: 99.66%
Example 8: Preparation of eslicarbazepine
[(S,S)-TsDpen-Ru(p-cymene)Cl] (50 mg, 0.000078 mol) was added to a stirred
suspension of oxcarbazepine (5.0 g, 0.01983 mol), dichloromethane (75 mL), and NNdimethylformamide
(10 mL) at 25°C to 30°C under nitrogen followed by drop-wise
addition of a premixed solution of formic acid and triethyl amine (5.6 mL:8 mL) in
dichloromethane (50 mL). After stirring at 25°C to 30°C for 15 minutes, the reaction
mixture was heated to reflux (39°C to 42°C) for 18 hours. The pH was maintained at 5.4
to 6.5 by the addition of formic acid (0.5 mL). After completion of the reaction, the
reaction mixture was washed with aqueous sodium bicarbonate (50 mL). The organic
layer was evaporated completely under reduced pressure at 40°C to 42°C to obtain the title
compound.
Yield: 4.3 g (86%)
Chromatographic Purity: 98.21%
Chiral purity: 100%
Example 9 : Preparation of eslicarbazepine
Oxcarbazepine (1.0 g, 0.00396 mol), aqueous sodium formate (27 g, 0.396 mol in
80 mL deionized water), and tetra-«-butylammonium bromide (3 g, 0.0093 mol) were
added to a stirred suspension of [(S,S)-TsDpen-Ru(p-cymene)Cl] (10 mg, 0.000014 mol),
dichloromethane (8 mL), and triethyl amine (10 mg, 0.000099 mol) at 25°C to 30°C under
nitrogen. After stirring at 25°C to 30°C for 15 minutes, the reaction mixture was heated to
38°C to 40°C overnight. After completion of the reaction, the reaction mixture was
washed with aqueous sodium bicarbonate (50 mL) and brine (50 mL). The organic layer
was evaporated completely under reduced pressure at 40°C to 42°C. The residue was
purified by column chromatography using dichloromethane as eluent to obtain the title
compound.
Yield: 0.58 g
Chromatographic Purity: 95.03%
Chiral purity: 99.51%
Example 10: Preparation of eslicarbazepine acetate
Acetone (6 mL) and 4-dimethylaminopyridine (0.028 g, 0.0000235 mol) were
added to a stirred suspension of the eslicarbazepine obtained by Example 9 (1.1 g, 0.00393
mol) at 25°C to 30°C. The reaction mixture was stirred at 25°C to 30°C and acetic
anhydride (0.6 g, 0.0051 mol) was added. The reaction mixture was stirred at 25°C to
30°C for 2 hours. After completion of the reaction, deionized water (22 mL) was charged
drop-wise and stirred for 3 hours at 10°C to 15°C. The reaction mixture was filtered and
washed with deionized water (15 mL). The solid thus obtained was suck dried and further
dried at 50°C to 55°C for 3 hours to obtain the title compound.
Yield: 0.45 g (35.4%)
Chromatographic Purity: 99.38%
Chiral purity: 99.7%
Example 11: Preparation of eslicarbazepine
Formic acid and triethyl amine (3.3 g:2.9 g) were added to a stirred suspension of
oxcarbazepine (3.0 g, 0.01 19 mol) and dichloromethane (45 mL) at 25°C to 30°C under
nitrogen. [(S,S)-TsDpen-RuQ?-cymene)Cl] (30 mg, 0.000047 mol) in NNdimethylformamide
(5.4 mL) was added to the reaction mixture. After stirring at 25°C to
30°C for 15 minutes, the reaction mixture was heated to reflux (39°C to 42°C) for 20
hours. After completion of the reaction, the reaction mixture was evaporated under
reduced pressure (500 mm/Hg to 700 mm/Hg) at 40°C to 42°C. Deionized water (60 mL)
was charged drop-wise and stirred for 2 hours at 0°C to 5°C. The reaction mixture was
filtered and washed with deionised water (20 mL). The solid obtained was suck dried and
further dried at 50°C to 55°C for 12 hours to obtain the title compound.
Yield: 2.53 g (84.3%)
Chromatographic Purity: 98.21%
Chiral purity: 100%
Example 12: Preparation of eslicarbazepine acetate
Acetone (6 mL) and 4-dimethylaminopyridine (0.048 g, 0.00004 mol) were added
to a stirred suspension of the eslicarbazepine obtained by Example 11 (1.5 g, 0.0059 mol)
at 25°C to 30°C. The reaction mixture was stirred at 25°C to 30°C and acetic anhydride
(0.8 g, 0.0071 mol) was added. The reaction mixture was stirred at 25°C to 30°C for 2
hours. After completion of the reaction, deionized water (27 mL) was charged drop-wise
and stirred for 3 hours at 0°C to 5°C. The reaction mixture was filtered and washed with
deionized water (15 mL). The solid obtained was suck dried and further dried at 50°C to
55°C for 3 hours to obtain the title compound.
Yield: 1.45 g (83.3%)
Chiral purity: 99.9%
Example 13: Preparation of eslicarbazepine
Formic acid and triethyl amine (2.2 g : 1.9 g) were added to a stirred suspension of
oxcarbazepine (2.0 g, 0.0079 mol) and dichloromethane (30 mL) at 25°C to 30°C under
nitrogen. [(S,S)-TsDpen-RuQ?-cymene)Cl] (20 mg, 0.00003 1 mol) in methanol (10 mL),
tetra-«-butylammonium bromide (200 mg), and water (2 mL) were added to the reaction
mixture. After stirring at 25°C to 30°C for 15 minutes, the reaction mixture was heated to
reflux (39°C to 42°C) for 24 hours. After completion of the reaction, the solvent was
completely evaporated under reduced pressure (500 mm/Hg to 700 mm/Hg) at 45°C to
47°C. Deionized water (30 mL) was charged drop-wise and stirred for 1 hour at 0°C to
5°C. The reaction mixture was filtered and washed with deionized water (20 mL). The
solid thus obtained was suck dried and further dried at 50°C to 55°C for 12 hours to obtain
the title compound.
Yield: 1.65 g (81.88%)
Chromatographic Purity: 99.76%
Chiral purity: 100%
Example 14: Preparation of eslicarbazepine
Formic acid and triethyl amine (2.2 g:1.9 g) were added to a stirred suspension of
oxcarbazepine (2.0 g, 0.0079 mol) and dichloromethane (30 mL) at 25°C to 30°C under
nitrogen. [(S,S)-TsDpen-RuQ?-cymene)Cl] (20 mg, 0.00003 1 mol) in ethyl acetate (10
mL), tetra-«-butylammonium bromide (200 mg), and water (2 mL) were added to the
reaction mixture. After stirring at 25°C to 30°C for 15 minutes, the reaction mixture was
heated to reflux for 30 hours. After completion of the reaction, the solvent was completely
evaporated under reduced pressure (500 mm/Hg to 700 mm/Hg) at 40°C to 42°C.
Deionized water (30 mL) was charged drop-wise and stirred for 2 hours at 0°C to 5°C.
The reaction mixture was filtered and washed with deionized water (20 mL). The solid
thus obtained was suck dried and further dried at 50°C to 55°C for 12 hours to obtain the
title compound.
Yield: 1.73g (85.8%)
Chromatographic Purity: 99.76%
Chiral purity: 100%
Example 15: Preparation of eslicarbazepine
A solution of triethyl amine (33.1 g, 0.327 mol) in dichloromethane (50 mL) was
slowly added to a stirred solution of formic acid (15.05 g, 0.327 mol) in dichloromethane
(1600 mL) at 25°C to 30°C under nitrogen. Oxcarbazepine (165 g, 0.654 mol) was added
to the reaction mixture. The reaction mixture was heated to reflux (38°C to 39°C) and
[(S,S)-TsDpen-RuQ?-cymene)Cl] (0.583 g, 0.0009167 mol) dissolved in NNdimethylformamide
(109 mL) was added to the reaction mixture at 38°C to 39°C. The
reaction mixture was further heated to reflux (40°C to 45°C) for about 38 hours and the
pH was adjusted to 6 to 7.5 every 3 hours to 6 hours using formic acid (33 mL). After
completion of the reaction, dichloromethane (830 mL) and N N-dimethylformamide (230
mL) were charged at 40°C to 45°C. After stirring for 15 minutes, 20% aqueous sodium
chloride solution (830 mL) was added and stirred for 15 minutes at 40°C to 45°C. The
reaction mixture was cooled to 30°C to 40°C and the organic layer was separated. The
aqueous layer was again extracted with dichloromethane (330 mL) and the combined
organic layer was evaporated under reduced pressure at 40°C to 50°C. The reaction
mixture was cooled (25°C to 30°C) and methanol (16.5 mL) was charged followed by the
slow addition of toluene (2500 mL). The reaction mixture was stirred for 2 hours at 25°C
to 30°C, filtered, and washed with toluene (330 mL). The solid obtained was suck dried
and further dried at 55°C to 60°C for 1 hours to obtain the title compound.
Yield: 148.1 g (89.1%)
Chromatographic Purity: 99.24%
Chiral purity: 100%

Claims:
1. A process for the preparation of eslicarbazepine acetate of Formula A
Formula A
which comprises:
a) hydrolysis of 10-methoxy-5H-dibenzo[Z?/]azepine-5-carboxamide of
Formula 3
Formula 3
with an organic acid selected from the group consisting of citric acid, tartaric
acid, or mixtures thereof to obtain oxcarbazepine of Formula 1;
Formula 1
b) asymmetric transfer hydrogenation of the oxcarbazepine of Formula 1 in the
presence of a catalyst and a hydride source in a mixture of
dichloromethane/NN -dimethylformamide, dichloromethane/water, or
dichloromethane/water/methanol to obtain eslicarbazepine of Formula 2; and
Formula 2
c) acylation of the eslicarbazepine of Formula 2 to obtain eslicarbazepine
acetate of Formula A.
2. The process according to claim 1, wherein the hydrolysis of 10-methoxy-5Hdibenzo[
Z J ]azepine-5-carboxamide of Formula 3 is performed in one or more solvents.
3. The process according to claim 2, wherein the solvent is selected from the group
consisting of water, esters, aromatic hydrocarbons, halogenated hydrocarbons, ketones,
ethers, polar aprotic solvents, or mixtures thereof.
4. The process according to claim 3, wherein the esters are selected from the group
consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
5. The process according to claim 3, wherein the aromatic hydrocarbons are selected
from the group consisting of toluene and xylene.
6. The process according to claim 3, wherein the halogenated hydrocarbons are
selected from the group consisting of dichloromethane, chloroform, and 1,2-
dichloroethane.
7. The process according to claim 3, wherein the ketones are selected from the group
consisting of acetone and methyl ethyl ketone.
8. The process according to claim 3, wherein the ethers are selected from the group
consisting of diethyl ether and tetrahydrofuran.
9. The process according to claim 3, wherein the polar aprotic solvents are selected
from the group consisting of N N-dimethylformamide, N N-dimethylacetamide,
dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.
10. The process according to claim 1, wherein step a) is performed at a temperature of
30°C to reflux.
11. The process according to claim 1, wherein the catalyst is selected from the group
consisting of [(S,S)-TsDpen-Ru(p-cymene)Cl], [(S,S)-teth-TsDpen-RuCl], RuCl[(S,S)-
FsDPEN](p-cymene), and RuCl[(S,S)-TsDPEN](mesitylene).
1 . The process according to claim 1, wherein the molar ratio of the catalyst to
oxcarbazepine is from about 0.0005 to about 0.1.
13. The process according to claim 1, wherein the hydride source is selected from the
group consisting of sodium acetate/water, formic acid/triethyl amine, potassium-ibutoxide/
isopropanol, potassium hydroxide/isopropanol, ammonium formate, and
ammonium acetate.
14. The process according to claim 1, wherein step b) is performed in the presence of a
phase transfer catalyst.
15. The process according to claim 1, wherein step c) involves treating the
eslicarbazepine with an acylating agent in the presence of a catalyst in one or more
solvents at a temperature of 25°C to reflux.
16. The process according to claim 15, wherein the solvent is selected from the group
consisting of water, esters, aromatic hydrocarbons, halogenated hydrocarbons, ketones,
ethers, polar aprotic solvents, or mixtures thereof.
17. The process according to claim 16, wherein the esters are selected from the group
consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
18. The process according to claim 16, wherein the halogenated hydrocarbons are
selected from the group consisting of dichloromethane, chloroform, and 1,2-
dichloroethane.
19. The process according to claim 16, wherein the ketones are selected from the
group consisting of acetone and methyl ethyl ketone.
20. The process according to claim 16, wherein the ethers are selected from the group
consisting of diethyl ether and tetrahydrofuran.
21. The process according to claim 16, wherein the polar aprotic solvents are selected
from the group consisting of N N-dimethylformamide, N N-dimethylacetamide,
dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.
22. The process according to claim 15, wherein the acylating agent is selected from the
group consisting of acetic anhydride or acetyl chloride.
23. The process according to claim 15, wherein the catalyst is 4-
dimethylaminopyridine.
A process for the preparation of oxcarbazepine of Formula 1
Formula 1
which comprises hydrolysis of 10-methoxy-5H-dibenzo[Z J ]azepine-5-carboxamide of
Formula 3
Formula 3
with an organic acid selected from the group consisting of citric acid, tartaric acid, or
mixture thereof.
25. The process according to claim 24, wherein the hydrolysis of 10-methoxy-5Hdibenzo[
Z J ]azepine-5-carboxamide of Formula 3 is performed in one or more solvents.
26. The process according to claim 25, wherein the solvent is selected from the group
consisting of water, esters, aromatic hydrocarbons, halogenated hydrocarbons, ketones,
ethers, polar aprotic solvents, or mixtures thereof.
27. The process according to claim 26, wherein the esters are selected from the group
consisting of ethyl acetate, n-propyl acetate, isopropyl acetate, and n-butyl acetate.
28. The process according to claim 26, wherein the aromatic hydrocarbons are selected
from the group consisting of toluene and xylene.
29. The process according to claim 26, wherein the halogenated hydrocarbons are
selected from the group consisting of dichloromethane, chloroform, and 1,2-
dichloroethane.
30. The process according to claim 26, wherein the ketones are selected from the
group consisting of acetone and methyl ethyl ketone.
31. The process according to claim 26, wherein the ethers are selected from the group
consisting of diethyl ether and tetrahydrofuran.
32. The process according to claim 26, wherein the polar aprotic solvents are selected
from the group consisting of N N-dimethylformamide, N N-dimethylacetamide,
dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.
33. The process according to claim 24, wherein the hydrolysis of 10-methoxy-5Hdibenzo[
b,f]azepine-5-carboxamide of Formula 3 is performed at a temperature of 30°C to
reflux.